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The gut microbiota reduces leptin sensitivity ...

The gut microbiota reduces leptin sensitivity and the expression of the obesity suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system

Schéle E, Grahnemo L, Anesten F, Hallén A, Bäckhed F, Jansson JO

Abstract

The gut microbiota contributes to fat mass and the susceptibility to obesity. However, the underlying mechanisms are not completely understood.To investigate if the gut microbiota affects hypothalamic and brainstem body fat regulating circuits, we compared gene expression of food intake regulating neuropeptides between germ-free and conventionally raised mice.We found that conventionally raised mice had decreased expression of the anti-obesity neuropeptide glucagon-like peptide-1 (GLP-1) precursor proglucagon (Gcg) in brainstem. Moreover, in both the hypothalamus and the brainstem, conventional mice had decreased expression of the anti-obesity neuropeptide brain-derived neurotrophic factor (Bdnf). Conventionally raised mice had reduced expression of the pro-obesity peptides neuropeptide-Y (Npy) and agouti-related protein (Agrp), and increased expression of the anti-obesity peptides pro-opiomelanocortin (Pomc) and cocain and amphetamine regulated transcript (Cart) in the hypothalamus. The changes in neuropeptide expression could be secondary to elevated fat mass in conventionally raised mice. Leptin treatment caused less weight reduction and less suppression of orexigenic Npy and Agrp expression in conventional mice compared with germ free mice. The hypothalamic expression of leptin resistance associated suppressor of cytokine signaling 3 (Socs-3) was increased in conventionally raised mice.In conclusion, the gut microbiota reduces the expression of two genes coding for body fat suppressing neuropeptides, Gcg and Bdnf, an alteration that may contribute to fat mass induction by the gut microbiota. Moreover, the presence of body fat inducing gut microbiota is associated with hypothalamic signs of Socs-3 mediated leptin resistance, which may be linked to failed compensatory body fat reduction.